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β(2)-integrin LFA1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection

Respiratory syncytial virus (RSV) bronchiolitis is the most common cause of infant hospital admissions, but there is limited understanding of the mechanisms of disease, and no specific antiviral treatment. Using a novel in vitro primary transepithelial neutrophil migration model and innovative imagi...

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Autores principales: Herbert, Jenny Amanda, Deng, Yu, Hardelid, Pia, Robinson, Elisabeth, Ren, Luo, Moulding, Dale, Smyth, Rosalind Louise, Smith, Claire Mary
Formato: Online Artículo Texto
Lenguaje:English
Publicado: European Respiratory Society 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406857/
https://www.ncbi.nlm.nih.gov/pubmed/32217648
http://dx.doi.org/10.1183/13993003.02216-2019
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author Herbert, Jenny Amanda
Deng, Yu
Hardelid, Pia
Robinson, Elisabeth
Ren, Luo
Moulding, Dale
Smyth, Rosalind Louise
Smith, Claire Mary
author_facet Herbert, Jenny Amanda
Deng, Yu
Hardelid, Pia
Robinson, Elisabeth
Ren, Luo
Moulding, Dale
Smyth, Rosalind Louise
Smith, Claire Mary
author_sort Herbert, Jenny Amanda
collection PubMed
description Respiratory syncytial virus (RSV) bronchiolitis is the most common cause of infant hospital admissions, but there is limited understanding of the mechanisms of disease, and no specific antiviral treatment. Using a novel in vitro primary transepithelial neutrophil migration model and innovative imaging methods, we show that RSV infection of nasal airway epithelium increased neutrophil transepithelial migration and adhesion to infected epithelial cells, which is associated with epithelial cell damage and reduced ciliary beat frequency, but also with a reduction in infectious viral load. Following migration, RSV infection results in greater neutrophil activation, degranulation and release of neutrophil elastase into the airway surface media compared to neutrophils that migrated across mock-infected nasal epithelial cells. Blocking of the interaction between the ligand on neutrophils (the β(2)-integrin LFA-1) for intracellular adhesion molecule (ICAM)-1 on epithelial cells reduced neutrophil adherence to RSV-infected cells and epithelial cell damage to pre-infection levels, but did not reduce the numbers of neutrophils that migrated or prevent the reduction in infectious viral load. These findings have provided important insights into the contribution of neutrophils to airway damage and viral clearance, which are relevant to the pathophysiology of RSV bronchiolitis. This model is a convenient, quantitative preclinical model that will further elucidate mechanisms that drive disease severity and has utility in antiviral drug discovery.
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spelling pubmed-74068572020-08-10 β(2)-integrin LFA1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection Herbert, Jenny Amanda Deng, Yu Hardelid, Pia Robinson, Elisabeth Ren, Luo Moulding, Dale Smyth, Rosalind Louise Smith, Claire Mary Eur Respir J Original Articles Respiratory syncytial virus (RSV) bronchiolitis is the most common cause of infant hospital admissions, but there is limited understanding of the mechanisms of disease, and no specific antiviral treatment. Using a novel in vitro primary transepithelial neutrophil migration model and innovative imaging methods, we show that RSV infection of nasal airway epithelium increased neutrophil transepithelial migration and adhesion to infected epithelial cells, which is associated with epithelial cell damage and reduced ciliary beat frequency, but also with a reduction in infectious viral load. Following migration, RSV infection results in greater neutrophil activation, degranulation and release of neutrophil elastase into the airway surface media compared to neutrophils that migrated across mock-infected nasal epithelial cells. Blocking of the interaction between the ligand on neutrophils (the β(2)-integrin LFA-1) for intracellular adhesion molecule (ICAM)-1 on epithelial cells reduced neutrophil adherence to RSV-infected cells and epithelial cell damage to pre-infection levels, but did not reduce the numbers of neutrophils that migrated or prevent the reduction in infectious viral load. These findings have provided important insights into the contribution of neutrophils to airway damage and viral clearance, which are relevant to the pathophysiology of RSV bronchiolitis. This model is a convenient, quantitative preclinical model that will further elucidate mechanisms that drive disease severity and has utility in antiviral drug discovery. European Respiratory Society 2020-08-06 /pmc/articles/PMC7406857/ /pubmed/32217648 http://dx.doi.org/10.1183/13993003.02216-2019 Text en Copyright ©ERS 2020 http://creativecommons.org/licenses/by/4.0/This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.
spellingShingle Original Articles
Herbert, Jenny Amanda
Deng, Yu
Hardelid, Pia
Robinson, Elisabeth
Ren, Luo
Moulding, Dale
Smyth, Rosalind Louise
Smith, Claire Mary
β(2)-integrin LFA1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection
title β(2)-integrin LFA1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection
title_full β(2)-integrin LFA1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection
title_fullStr β(2)-integrin LFA1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection
title_full_unstemmed β(2)-integrin LFA1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection
title_short β(2)-integrin LFA1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection
title_sort β(2)-integrin lfa1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406857/
https://www.ncbi.nlm.nih.gov/pubmed/32217648
http://dx.doi.org/10.1183/13993003.02216-2019
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